tbuckley/cabot-search huggingface dataset:
Survival outcomes with observation or adjuvant therapy in elderly patients with biliary tract cancer.
Authors: Olumide B. Gbolahan, Xiaojie Zhi, Gehan Botrus, Mihir Maheshkumar Shah, Juan Sarmiento, Maria C. Russell, David A. Kooby, Shishir K. Maithel, Olatunji B. Alese
Journal: Journal of Clinical Oncology (2023)

e16230 Background: The impact of adjuvant therapy (AT) on overall survival (OS) for biliary tract cancer (BTC) is contested. The BILCAP study suggested an improvement in OS with adjuvant capecitabine compared to observation. This was not apparent in the intention to treat population. Importantly, none of the patients in the study was older than 70 years. Considering the toxicity of AT and conflicting results of efficacy, the role of AT in older adults with BTC needs to be thoroughly assessed. We hypothesized that AT is not associated with significant benefit in the elderly. Methods: We performed a retrospective review of patients with resected BTC; gall bladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) using the National Cancer Database (NCDB) PUFs (2004-2019). We limited analysis to patients aged &gt;= 70 years. We compared clinical characteristics and outcomes in those who received AT (including chemotherapy and chemotherapy + radiation) within 6 months after resection, and those who did not (Obs). We performed propensity score matching analysis of both groups (matched for age, sex, race, Charleson-Deyo score, AJCC pathologic T stage among others) and assessed survival by Kaplan-Meier analysis. Results: We identified 8,091 elderly patients with T1-T3/N1-N2 resected BTC. The majority had GBC (76.7%), and 3, 041 (38%) were aged &gt;= 80 years (median 78 years). Only 2, 632 (32.5%) received AT. Of these, 1,304 (50%) received chemotherapy and radiation. Median OS was higher in the Obs vs the AT group (24.3 months, vs 20.2 months, P &lt; 0.0001) and the five-year survival was also higher in the Obs group (29.1% vs 22.6%, P&lt;0.001). Survival also favored the Obs group in a propensity score matched cohort of 835 patients per group (median OS 33.1 vs 19.5 months, P &lt;0.0001). On multivariable analysis AT was associated with a higher hazard of death (HR 1.21, CI 1.13-1.29, P &lt;0.001). Age &gt;=80 (HR 1.39, CI 1.32-1.47, P&lt;0.001), GBC ( HR 1.29, CI 1.20-1.39, P&lt;0.001) were also associated with worse survival. Compared to diagnosis between 2004-2009 diagnosis in 2010- 2015 (HR 0.83, CI 0.78- 0.89) and 2016- 2019 (HR 0.74 CI 0.67-0.8, P &lt;0.001) were associated with improved OS. Conclusions: In patients &gt;=70, AT for BTC was not associated with improved OS and was actually associated with a higher hazard of death compared Obs. Based on these results, the role of AT for BTC in the elderly needs to be examined prospectively.
Chemotherapy combined with anlotinib, toripalimab and stereotactic radiotherapy in oligo-metastatic nasopharyngeal carcinoma: A prospective, multicenter phase II clinical study.
Authors: Dong Yang, Xueying Hu, Lin Ruan, Zhendong Yang, Tingting Zhang, Yutao Qin, Kang Liu, Fangfang Liang, Yating Qin, Heqing Huang, Pian Li, Guobo Du, Ying Lu, Yaqian Han, Rensheng Wang, Min Kang
Journal: Journal of Clinical Oncology (2023)

e18011 Background: Distant metastasis is the main cause of nasopharyngeal carcinoma (NPC) related death while there are few treatment options for it. How to further improve the survival of NPC patients with distant metastases is an urgent problem to be solved in clinical practice. This study investigated the efficacy and safety of chemotherapy in combination with anlotinib (a multi-target tyrosine kinase inhibitor), toripalimab, and stereotactic radiotherapy(SBRT) in treatment of metastatic NPC. Methods: This is a prospective, multi-centered, single-arm, phase II trial (ChiECRCT20210147). Patients with histologically confirmed non-keratinous carcinoma and post-treatment metastatic NPC (stage IVb, AJCC 8th) who had no local recurrence and received no systemic antitumor therapy for metastatic lesions previously were enrolled. No more than 5 metastatic lesions (metastatic sites include lung, liver, bone, etc.), and with at least one measurable target lesion according to RECIST1.1. Other inclusion criteria included 18-65 years old and ECOG 0-1. All patients received gemcitabine (1000 mg/m 2 , ivgtt, d1/8), cisplatin (80 mg/m 2 , ivgtt, d1), toripalimab (240mg, ivgtt, d1) and anlotinib (12mg, oral, qd, d1-14) every 3 weeks for 6 cycles, then followed by toripalimab (240mg, ivgtt, d1) and anlotinib (12mg, oral, qd, d1-14) every 3 weeks for 11 cycles. The SBRT was initiated after 2 cycles of chemotherapy (bone GTV 30-45Gy/3-5f, liver and lung GTV 45-60Gy/4-6f). The primary endpoint was objective response rate (ORR). Here we report the results of a preliminary analysis. Results: Between January 2022 and January 2023, a total of 19 patients were enrolled (13 males and 6 females), the median age was 46 years old. At the data cutoff date on January 31, 2023, 15 patients were eligible for the evaluation of tumor response with metastatic lesions. 100% of the patients (15 of 15) had a response and the confirmed ORR was 100% (complete response, n = 4; partial response, n = 11) for metastatic lesions. The most common treatment-related adverse events (TRAE) of any grade were leukopenia (15 of 15,100%), anaemia(13 of 15, 93.3%), decreased appetite (10 of 15, 66.7%), hypothyroidism (6 of 15, 40.0%), rash(5 of 15, 33.3%) and pneumonitis (5 of 15, 33.3%). Grade 3-4 TRAE included leukopenia (3 of 15, 20.0%) and no fatal adverse events occurred. Conclusions: This preliminary analysis indicated that chemotherapy combined with anlotinib, toripalimab, and stereotactic radiotherapy had promising efficacy and favorable tolerance as treatment of oligo-metastatic NPC. Clinical trial information: ChiECRCT20210147 .
Cancer pain in the emergency department: An EMR-based opioid dosing intervention and the effects on patient outcomes.
Authors: Christopher John Coyne, Ryan Miller, Kelly Dong, Rebecca Arielle Shatsky
Journal: Journal of Clinical Oncology (2023)

e24167 Background: Pain is a common reason for patients with cancer to seek care in the Emergency Department (ED). Many of these patients are on chronic opioids and may have developed opioid tolerance, which makes appropriate dosing challenging for emergency physicians. Therefore, we designed an electronic medical record (EMR) based best practice advisory (BPA) intervention to recommend appropriate opioid dosing in the ED, based on a patient’s prescription opioid use. Methods: We conducted a retrospective cohort study to evaluate our cancer pain intervention at two academic EDs from May 2020 to May 2022. Our novel BPA algorithm identified ED cancer patients who were taking prescription opioids with an EMR-calculated morphine equivalent daily dose (MEDD) of at least 100. If an ED provider ordered an opioid for one of these patients, the BPA would fire and recommend an opioid dose based on the patient’s individual MEDD. The ED provider would then have the option of accepting or cancelling the BPA. We compared outcomes based on whether patients received BPA-guided increased opioid dosing. We utilized the chi-squared test with an alpha of &lt; 0.05 to assess the relationship between BPA-guided increased opioid dosing and pain scores, hospital admission rates and ED bounce-back rates (return visit within 7 days). Results: We identified 399 patients who met our inclusion criteria, representing 705 BPA alerts. Those patients that received increased opioid dosing were similar to those that did not, with respect to age, sex, race/ethnicity and ECOG score. Patients who received BPA-guided increased opioid dosing experienced a greater improvement in pain (72.5% vs 65.1%, p = 0.03) and were admitted less frequently (58.5% vs 63.9%, p = 0.04). However, among discharged patients, those that received increased opioid dosing bounced back to the ED more frequently (16.2% vs 7.7%, p &lt; .01). Conclusions: This EMR-based BPA intervention was associated with improved pain scores and decreased admission rates among cancer patients visiting the ED. The same intervention, however, was associated with increased ED return visits within 7 days, suggesting that pain management strategies may need to be implemented or modified upon ED discharge to assure that patients’ symptoms are adequately managed at home.
Clinical validity of TTMV-HPV DNA liquid biopsies for the diagnosis and surveillance of HPV-associated oropharyngeal carcinoma.
Authors: Scott A. Roof, Rocco Ferrandino, Sida Chen, Catharine Kappauf, Joshua Barlow, Brandon Gold, William Westra, Michael Berger, Marita S Teng, Mohemmed N Khan, Richard Lorne Bakst, Kunal K. Sindhu, Eric Michael Genden, Raymond L Chai, Marshall R. Posner, Krzysztof Misiukiewicz
Journal: Journal of Clinical Oncology (2023)

6060 Background: While there are several HPV biomarker assays, a commercially available assay evaluating tumor tissue modified viral DNA (TTMV-HPV DNA) (NavDx, Naveris Inc, Natick, MA) has shown impressive results in clinical trials and small cohort studies. Our aim was to establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary, real-world clinical setting. Methods: In this retrospective analysis, we evaluated the accuracy of the TTMV-HPV DNA assay in detecting HPVOPSCC in the diagnostic (pre-treatment) and surveillance phases of care between April 2020 and October 2022. For the diagnostic cohort, patients with OPSCC and at least one TTMV-HPV DNA measurement prior to initiation of primary therapy were included in the analysis. For the surveillance cohort, all TTMV-HPV DNA tests performed 3 months after completion of primary therapy for pathologically confirmed HPV-associated OPSCC were evaluated, regardless of pre-treatment TTMV-HPV DNA testing. Patients with suspected recurrence, but without pathologic confirmation, were excluded. HPV status was defined utilizing positive p16 staining on immunohistochemistry (93.2% diagnosis; 97.9% surveillance) or HPV polymerase chain reaction/in situ hybridization (79.6% diagnosis; 89.7% surveillance). Results: In the diagnostic cohort, 163 patients were included. The cohort included mostly men (87%) with median age 63, of which 93.3% had HPVOPSCC versus 6.7% had HPV negative OPSCC. The sensitivity in pre-treatment diagnosis was 91.5%; its specificity was 100%. In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. 23 patients had pathologically confirmed recurrences. The assay demonstrated 79.2% sensitivity and 100% specificity in detecting the recurrences. Positive predictive value was 100% and negative predictive value was 98.2%. The median lead time from positive test to pathologic confirmation was 28 days, 6/18 (30%) had lead time &gt;50 days (maximum 507 days). Conclusions: The commercially available NavDx TTMV-HPV DNA assay demonstrated 100% specificity, and therefore excellent positive predictive value, in both diagnosis and surveillance. However, the sensitivity was lower, 91.5% for the diagnosis cohort and 79.2% for the surveillance cohort, signifying that a negative value may require further work-up. Further studies will be required to determine the optimal timing of testing and how results should inform treatment decisions. [Table: see text]
Correlating peptidylglycine alpha-amidating monooxygenase (PAM) expression with clinicopathologic variables in gastrointestinal (GI) neuroendocrine tumors (NETs).
Authors: Jordan Sim, Horia Marginean, Anna Jirovec, Michael M. Vickers, E. Celia Marginean, Tim Asmis, Bianca Marginean, Rachel Anne Goodwin
Journal: Journal of Clinical Oncology (2023)

e16243 Background: Peptidylglycine alpha-amidating monooxygenase (PAM) is a hypoxia-responsive protein which is responsible for peptide alpha-amidation, important in neuroendocrine hormone maturation. A prior study of well-differentiated neuroendocrine tumors of multiple sites, both GI and non-GI, has shown that PAM expression by immunohistochemistry correlates with important clinical and pathologic parameters. We assessed PAM expression by immunohistochemistry using two separate scoring systems in patients with well-differentiated neuroendocrine tumors (NETs) exclusively of the GI tract and assessed its correlation with clinical and pathologic variables. Methods: A tissue microarray was constructed from 58 patients with NETs of the GI tract. Two separate scoring systems were used, the immunoreactive score (IRS) and one as described by Horton et al (2020). The IRS score was derived by scoring for intensity (range 0-3) and percent of cells staining (range 0-4), multiplying these to give an overall IRS between 0 and 12. These results were dichotomized into 0-1 (negative) and 2-12 (positive). The score as described by Horton et al is a 4-tiered system: 0, no staining; 1, very faint and scarce staining; 2, staining easily visible in &gt; 50% of tissue; 3, moderately dark and intense staining across 50% of tissue; 4, very intense dark staining across &gt; 50% of tissue. These were then divided into negative (0), low (1) and high (2-4) scores. Clinical and pathologic variables were collected from the clinical records and correlated with PAM staining. Results: Patients had NETs involving the stomach (n = 1), duodenum (n = 3), ileum (n = 18), small bowel (n = 12), cecum (n = 2), and pancreas (n = 13). Twenty-one patients (36.2%) had 1 metastatic site, 12 patients (20.7%) had &gt; = 2 metastatic sites and 25 patients (43.1%) lacked metastases. IRS and Horton scores were compared and were correlated (p = 0.007). By IRS, 9 patients (31%) had negative staining, and 20 patients (69%) had positive PAM staining. PAM staining did not correlate with functional status of the tumor (p = 1), synchronicity of disease (p = 1), number of metastatic sites (p = 0.69), Octreotide receptor positivity (p = 0.72) or blood chromogranin A (p = 0.58) and urine 5 HIAA levels (p = 0.52). PAM scoring also did not correlate with Ki-67 of primary tumors (p = 0.57). Conclusions: In our GI NET cohort, PAM staining did not correlate with any of the assessed clinical variables or with Ki-67 of primary tumors. A previous study of NETs involving more body sites found that PAM staining did inversely correlate with Ki-67 scoring. This difference may be due to our assessment of solely gastrointestinal NETs.
Association of encapsulation of CDK12 inhibitor with anti-tumour activity in colon cancer cell lines.
Authors: Pedro Pérez-Segura, Cristina Diaz-Tejeiro, Alberto Ocana, Adrián Sanvicente, María Arenas-Moreira, Carlos Alonso Moreno, Cristina Nieto Jiménez
Journal: Journal of Clinical Oncology (2023)

e15077 Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Unfortunately, despite the incorporation of new therapeutic options, the metastatic setting is still an incurable disease. Cyclin-dependent kinases (CDKs) are a large family of proteins involved in cell cycle and transcriptional regulation, and are highly expressed in colon cancer, such as CDK12. Here, we explore the antitumor activity of a novel CDK12 inhibitor (CDK12-IN-E9) in preclinical models of colon cancer, and its liposomal formulation (LP-CDK12-IN-E9). Methods: Expression of CDK12 at a genomic level was assessed using web tools such as the Colonomics database. CDK12-IN-E9 was encapsulated in a liposomal formulation to evaluate differences between the free and the liposome form. The effect of compounds on cell viability was assessed with MTT assays. Matrigel assays were performed to study invasiveness and wound assays for migration. In addition, cell cycle and apoptosis studies were carried out by flow cytometry with 7-AAD, annexin V staining, and western-blot for specific protein expression. DNA damage and caspase degradation assays were performed by immunofluorescence. Results: Genomic mapping of CDK12 showed a higher expression in CRC than in normal tissue ( p−value = 1.424e−43). The CDK12 inhibitor was formulated in liposomes LP-CDK12-IN-E9 with the following characteristics: a polydispersity index of 0.11 ±0.02, a hydrodynamic radius of 62.98 ±10.29 nm and a zeta potential of -27.12±1.65 mV. CDK12-IN-E9 induced an antiproliferative effect in SW620, SW480 and HCT116 colon cancer cell lines. LP-CDK12-IN-E9 displayed an EC50 two times higher compared to CDK12-IN-E9 and a higher reduction of invasiveness between free inhibitor and its liposomal formulation mainly in HCT116 ( p-value &lt; 0.001). Cell cycle studies showed no significant differences between CDK12-IN-E9 and LP-CDK12-IN-E9, but there was a profound induction of cell death at the highest doses through apoptosis mediated largely by caspases. In parallel to the effect on cell death, an increase in histone H2AX phosphorylation and an increase in cleaved caspase-3 was observed, which also implies a large increase in DNA damage in tumor cells. In vivo studies are ongoing. Conclusions: In summary, LP- CDK12-IN-E9 showed more antitumoral activity than its free formulation in CRC cell lines mainly through a caspase-dependent induction of apoptosis. This data suggests that liposomal formulation of novel chemical entities can augment its antitumoral properties.
Long-term outcomes of tepotinib in patients with <i>MET</i> exon 14 skipping NSCLC from the VISION study.
Authors: Paul K. Paik, Marina Chiara Garassino, Xiuning Le, Michael Thomas, Hiroshi Sakai, Remi Veillon, Egbert F. Smit, Julien Mazieres, Alexis B Cortot, Jo Raskin, Santiago Viteri, James Chih-Hsin Yang, Myung-Ju Ahn, Yi-Long Wu, Jun Zhao, Svenja Adrian, Karin Berghoff, Rolf Bruns, Andreas Johne, Enriqueta Felip
Journal: Journal of Clinical Oncology (2023)

9060 Background: Tepotinib is a highly selective MET inhibitor with clinical activity in patients (pts) with MET exon 14 ( METex14) skipping NSCLC. We previously reported robust and durable activity of tepotinib from the Phase II VISION study (NCT02864992; data cut: Feb 20, 2022; median follow-up: 26.1 months [mos]; Thomas, et al. WCLC 2022). Here, we report long-term outcomes from VISION, fulfilling an FDA post-market requirement (data cut: Nov 20, 2022; follow-up: Cohort A [primary cohort] ≥35 mos, Cohort C [confirmatory cohort] ≥18 mos). Methods: Pts with advanced METex14 skipping NSCLC detected by liquid and/or tissue (T+) biopsy received tepotinib 500 mg (450 mg active moiety) once daily. The primary endpoint was objective response by independent review using RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Of 313 pts enrolled, median age was 72 years (range 41–94) and pts received tepotinib for a mean (standard deviation [SD]) of 11.5 mos (11.6); median follow-up was 32.6 mos (range 0.3–71.9). First line (1L) pts (n=164; median age: 74 years [range 47–94]; male: 50.6%; ECOG PS 1: 72.0%; smoking history: 53.7%) received tepotinib for a mean (SD) of 12.4 mos (12.2), with 27 pts still receiving treatment. ORR was 57.3% (95% CI: 49.4, 65.0), mDOR was 46.4 mos (13.8, not estimable [ne]), mPFS was 12.6 mos (9.7, 17.7), and mOS was 21.3 mos (14.2, 25.9). Among 111 1L T+ pts, ORR was 58.6% (48.8, 67.8), mDOR was 46.4 mos (15.2, ne), mPFS was 15.9 mos (11.0, 49.7), and mOS was 29.7 mos (18.8, ne) (Table). Second-or-later line (2L+) pts (n=149; median age: 71 years [range 41–89]; male: 47.7%; ECOG PS 1: 75.8%; smoking history: 40.9%) received tepotinib for a mean (SD) of 10.5 mos (11.0), with 10 pts still receiving treatment. ORR was 45.0% (36.8, 53.3) and mDOR was 12.6 mos (9.5, 18.5). Across all 313 pts, ORR was 51.4% (45.8, 57.1), mDOR was 18.0 mos (12.4, 46.4), mPFS was 11.2 mos (9.5, 13.8), and mOS was 19.6 mos (16.2, 22.9). No new safety concerns were observed. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 34.8% of pts; 14.7% of pts discontinued treatment due to TRAEs. Any grade related peripheral edema occurred in 67.1% of pts (Grade ≥3: 11.2%). Conclusions: The long-term outcomes of VISION demonstrate the robust and durable clinical activity of tepotinib, particularly in 1L T+ pts, and manageable safety profile, further defining its use in clinical practice. Clinical trial information: NCT02864992 . [Table: see text]
3D genomics identify alternate mechanisms of homologous recombination deficiency in uterine sarcoma.
Authors: Sarah Chiang, Martee Leigh Hensley, Varshini Vasudevaraja, Ivy Tran, Yiying Yang, Colin JR Stewart, Kay J Park, Lora H Ellenson, Kristin Sikkink, Anthony Schmitt, Matija Snuderl
Journal: Journal of Clinical Oncology (2023)

e17624 Background: Uterine sarcomas are rare tumors with diverse morphologic appearances, genetic underpinnings, and clinical behavior. Molecular characterization of these tumors by next generation sequencing (NGS) has improved disease classification and prognostication, but its impact on therapeutic selection remains limited. Analysis of 3D genomics datasets has recently been shown to detect large complex structural variants (SV) and chromatin architecture in normal and diseased human tissues. We applied genome-wide chromosome conformation capture (Hi-C) techniques in a variety of uterine sarcomas to identify novel therapeutic targets. Methods: Formalin-fixed paraffin-embedded tissue from 48 primary or recurrent uterine sarcomas were subjected to Hi-C to identify chromosomal rearrangements. The cohort included leiomyosarcoma (LMS, n = 7), adenosarcoma (AS, n = 7), endometrial stromal sarcoma (n = 7; high grade (HGESS), n = 4; low grade (LGESS), n = 3), sarcoma not otherwise specified (n = 17; high grade (HGNOS), n = 10, low grade (LGNOS), n = 7), undifferentiated uterine sarcoma (UUS, n = 6) and heterologous sarcoma (n = 2). Tumors were previously subjected to targeted DNA (n = 10) and/or RNA (n = 26) NGS with no therapeutic targets identified and only BCOR internal tandem duplication detected in a HGESS. Results: Hi-C detected SV in 73% of uterine sarcomas (n = 35/48), including those previously negative by targeted RNA NGS (n = 25/26). Homologous recombination repair (HRR) gene alterations were detected by Hi-C in 42% of tumors (n = 20/48), including AS (n = 5/7), HGESS (n = 2/4), LGESS (n = 1/3), LMS (n = 2/7), UUS (n = 2/6), heterologous sarcoma (n = 1/2), HGNOS (n = 3/10) and LGNOS (n = 1/7). SV included gene (gene to gene, n = 3; gene to non-coding DNA, n = 8) and proximity (n = 13) fusions disrupting HRR genes ( ATM, BRIP1, CDK12, CHEK1, CHEK2, NBN, PARP3, RAD51B, RAD51C, RAD51D) with enrichment for RAD51B fusions (50%, n = 10/20). Among all tumors with HRR gene alterations detected by Hi-C, only one uterine sarcoma harbored a missense ATM mutation by targeted DNA NGS (n = 1/5). Conclusions: Molecular characterization of uterine sarcomas by Hi-C may uncover HRR gene alterations not currently detectable by targeted DNA and RNA NGS. Homologous recombination deficiency (HRD) is not limited to LMS and may frequently result from SV, particularly between HRR gene to non-coding DNA in a variety of uterine sarcomas. These alternate mechanisms for HRD may serve as a potential therapeutic biomarker for HRD-targeted therapy in uterine sarcoma.